Cancer is the second leading cause of death behind heart disease. In fact, cancer incidence and death figures account for about 10% of the U.S. population in certain areas of the United States (National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database and Bureau of the Census statistics; see, Harrison's Principles of Internal Medicine, Kasper et al., 16th ed., 2005, Chapter 66). The five leading causes of cancer deaths among men are lung cancer, prostate cancer, colon and rectum cancer, pancreatic cancer, and leukemia. The five leading causes of cancer deaths among women are lung cancer, breast cancer, colon cancer, ovarian cancer, and pancreatic cancer. When detected at locally advanced or metastatic stages, no consistently curative treatment regimen exists. Treatment for metastatic cancer includes immunotherapy, hormonal ablation, radiation therapy, chemotherapy, hormonal therapy, and combination therapies.
Cyclophosphamide (Cytoxan) is a widely used anti-cancer chemotherapy drug and standard agent to treat many cancers, including breast cancer. Cyclophosphamide is an alkylating agent that is metabolically activated by being converted into phosphoramide mustard and acrolein. These active metabolites slow the growth of cancer cells by preventing cell division in a cell-cycle phase-nonspecific manner (see, e.g., Moore, Clin. Pharmacokinet., vol. 20, 194-208, 1991).
5-fluorouracil (fluorouracil) is an anti-cancer chemotherapy drug that is used to treat several types of cancers, including breast cancer. 5-fluorouracil is a pro-drug that is converted to an active drug by metabolism. The active metabolites primarily function by inactivating thymidylate synthase, causing DNA damage which induces cell cycle arrest and apoptosis of cancer cells (see, e.g., Peters et al., Biochim. Biophys. Acta, vol. 1587, 194-205, 2002).
Doxorubicin (adriamycin) is a widely used anti-cancer chemotherapy drug and a standard agent to treat many cancers, including breast cancer. The drug targets topoisomerase II and causes DNA damage. Doxorubicin also targets mitochondria and causes oxidative stress. This latter mechanism is thought to account for both therapeutic efficacy and systemic toxicity. It has been shown that overexpression of manganese superoxide dismutase (MnSOD), an antioxidant enzyme with mitochondrial localization, protects against doxorubicin toxicity and makes cancer cells resistant to doxorubicin treatment (see, e.g., Hur et al., Clin Cancer Research, vol. 9, 5768-5775, 2003; Suresh et al., British J Haematology, vol. 120, 457-463, 2003; Yen et al., J Clin Invest., vol. 98, 1253-1260, 1996).